2-chloro-5-[{6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl}amino]benzo-1,4-quinone | 872332-22-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 2-chloro-5-[{6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl}amino]benzo-1,4-quinone
• 英文别名: 2-Chloro-5-[[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]amino]cyclohexa-2,5-diene-1,4-dione
• CAS: 872332-22-4
• 化学式: C₂₂H₂₃ClN₄O₄
• 分子量: 442.902
• InChiKey: UYOQKICXCYZSAY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  31
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  93.6
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  2-chloro-5-[{6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl}amino]benzo-1,4-quinone 、 1,3-二氟-2-丙醇 在 sodium phenoxide 作用下， 以 氯仿 为溶剂， 反应 2.0h， 生成 2-[2-fluoro-1-(fluoromethyl)ethoxy]-5-([6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]amino)benzo-1,4-quinone
  参考文献：
  名称：

  2-(Quinazolin-4-ylamino)-[1,4]benzoquinones as Covalent-Binding, Irreversible Inhibitors of the Kinase Domain of Vascular Endothelial Growth Factor Receptor-2

  摘要：

  A series of 2-(quinazolin-4-ylamino)-[1,4] benzoquinone derivatives that function as potent covalent-binding, irreversible inhibitors of the kinase domain of vascular endothelial growth factor receptor-2 (VEGFR-2) has been prepared by ceric ammonium nitrate oxidation of substituted (2,5-dimethoxyphenyl)(6,7-disubstituted-quinazolin-4-yl)amines and by displacement of the chlorine atom of substituted 2-chloro-5-(6,7-disubstituted-quinazolin-4-ylamino)-[1,41benzoquinones with various amines, anilines, phenols, and alcohols. Enzyme studies were conducted in the absence and presence of glutathione and plasma. Several of the compounds inhibit VEGF-stimulated autophosphorylation in intact cells. Kinetic experiments were performed to study the reactivity of selected inhibitors toward glutathione. Reactivities correlated with LUMO energies calculated as averages of those of individual conformers weighted by the Boltzmann distribution. These results and molecular modeling were used to rationalize the biological observations. The compounds behave as non-ATP-competitive inhibitors. Unequivocal evidence, from mass spectral studies, indicates that these inhibitors form a covalent interaction with Cys-1045. One member of this series displays antitumor activity in an in vivo model.

  DOI：

  10.1021/jm050559f
• 作为产物：
  描述：

  4-氯-2,5-二甲氧基苯胺 在 吡啶 、 ammonium cerium(IV) nitrate 、 sodium hexamethyldisilazane 、 三乙酰氧基硼氢化钠 、 溶剂黄146 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 乙腈 、 叔丁醇 为溶剂， 反应 28.75h， 生成 2-chloro-5-[{6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl}amino]benzo-1,4-quinone
  参考文献：
  名称：

  2-(Quinazolin-4-ylamino)-[1,4]benzoquinones as Covalent-Binding, Irreversible Inhibitors of the Kinase Domain of Vascular Endothelial Growth Factor Receptor-2

  摘要：

  A series of 2-(quinazolin-4-ylamino)-[1,4] benzoquinone derivatives that function as potent covalent-binding, irreversible inhibitors of the kinase domain of vascular endothelial growth factor receptor-2 (VEGFR-2) has been prepared by ceric ammonium nitrate oxidation of substituted (2,5-dimethoxyphenyl)(6,7-disubstituted-quinazolin-4-yl)amines and by displacement of the chlorine atom of substituted 2-chloro-5-(6,7-disubstituted-quinazolin-4-ylamino)-[1,41benzoquinones with various amines, anilines, phenols, and alcohols. Enzyme studies were conducted in the absence and presence of glutathione and plasma. Several of the compounds inhibit VEGF-stimulated autophosphorylation in intact cells. Kinetic experiments were performed to study the reactivity of selected inhibitors toward glutathione. Reactivities correlated with LUMO energies calculated as averages of those of individual conformers weighted by the Boltzmann distribution. These results and molecular modeling were used to rationalize the biological observations. The compounds behave as non-ATP-competitive inhibitors. Unequivocal evidence, from mass spectral studies, indicates that these inhibitors form a covalent interaction with Cys-1045. One member of this series displays antitumor activity in an in vivo model.

  DOI：

  10.1021/jm050559f

文献信息

• 2-(Quinazolin-4-ylamino)-[1,4]benzoquinones as Covalent-Binding, Irreversible Inhibitors of the Kinase Domain of Vascular Endothelial Growth Factor Receptor-2
  作者：Allan Wissner、M. Brawner Floyd、Bernard D. Johnson、Heidi Fraser、Charles Ingalls、Thomas Nittoli、Russell G. Dushin、Carolyn Discafani、Ramaswamy Nilakantan、Joseph Marini、Malini Ravi、Kinwang Cheung、Xingzhi Tan、Sylvia Musto、Tami Annable、Marshall M. Siegel、Frank Loganzo

  DOI：10.1021/jm050559f

  日期：2005.12.1

  A series of 2-(quinazolin-4-ylamino)-[1,4] benzoquinone derivatives that function as potent covalent-binding, irreversible inhibitors of the kinase domain of vascular endothelial growth factor receptor-2 (VEGFR-2) has been prepared by ceric ammonium nitrate oxidation of substituted (2,5-dimethoxyphenyl)(6,7-disubstituted-quinazolin-4-yl)amines and by displacement of the chlorine atom of substituted 2-chloro-5-(6,7-disubstituted-quinazolin-4-ylamino)-[1,41benzoquinones with various amines, anilines, phenols, and alcohols. Enzyme studies were conducted in the absence and presence of glutathione and plasma. Several of the compounds inhibit VEGF-stimulated autophosphorylation in intact cells. Kinetic experiments were performed to study the reactivity of selected inhibitors toward glutathione. Reactivities correlated with LUMO energies calculated as averages of those of individual conformers weighted by the Boltzmann distribution. These results and molecular modeling were used to rationalize the biological observations. The compounds behave as non-ATP-competitive inhibitors. Unequivocal evidence, from mass spectral studies, indicates that these inhibitors form a covalent interaction with Cys-1045. One member of this series displays antitumor activity in an in vivo model.